Axin downregulates TCF-4 transcription via beta-catenin, but not p53, and inhibits the proliferation and invasion of lung cancer cells.
Axin downregulates TCF-4 transcription via beta-catenin, but not p53, and inhibits the proliferation and invasion of lung cancer cells.
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DOI：
10.1186/1476-4598-9-25
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发表时间：
2010-02-02
期刊：
影响因子：
37.3
通讯作者：
Wang EH
中科院分区：
文献类型：
--
作者：
Yang LH;Xu HT;Han Y;Li QC;Liu Y;Zhao Y;Yang ZQ;Dong QZ;Miao Y;Dai SD;Wang EH
我们以前报道过Axin的过度表达下调T细胞因子-4（TCF-4）的转录。然而，Axin下调TCF-4转录和表达的机制尚不清楚。已有报道β-catenin促进TCF-4的转录，而p53抑制TCF-4的转录。本研究的目的是研究β-catenin和/或p53是否是Axin介导的TCF-4下调所必需的。缺乏p53/HIPK 2和/或β-连环蛋白结合结构域的轴蛋白突变体在肺癌细胞BE 1（突变型p53）和A549（野生型p53）中表达。在BE 1细胞中，Axin或AxinΔp53的表达下调β-catenin和TCF-4，而β-catenin的敲低上调TCF-4。然而，AxinΔβ-ca在BE 1细胞中的表达并不下调TCF-4的表达。这些结果表明Axin通过β-catenin下调TCF-4转录。尽管野生型p53的过表达也下调了BE 1细胞中的TCF-4，但p53和AxinΔβ-ca的共转染并没有进一步下调TCF-4。这些结果表明，Axin不促进p53介导的TCF-4下调。Axin、AxinΔp53和AxinΔβ-ca均下调A549细胞中的β-catenin和TCF-4。p53基因敲除可上调β-catenin和TCF-4的表达，而AxinΔβ-ca和p53 siRNA共转染则可下调β-catenin和TCF-4的表达。这些结果表明p53不是Axin介导的TCF-4下调所必需的。GSK-3β的敲低或抑制阻止了Axin介导的TCF-4下调。Axin和AxinΔp53的表达抑制了BE 1和A549的增殖和侵袭能力，AxinΔβ-ca的表达仅能有效抑制BE 1和A549的增殖和侵袭能力。Axin通过β-catenin下调TCF-4的转录，并且不依赖于p53。Axin还可能通过β-catenin和p53抑制肺癌细胞的增殖和侵袭。
We previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription. However, the mechanism(s) by which Axin downregulates the transcription and expression of TCF-4 is not clear. It has been reported that β-catenin promotes and p53 inhibits TCF-4 transcription, respectively. The aim of this study was to investigate whether β-catenin and/or p53 is required for Axin-mediated downregulation of TCF-4. Axin mutants that lack p53/HIPK2 and/or β-catenin binding domains were expressed in lung cancer cells, BE1 (mutant p53) and A549 (wild type p53). Expression of Axin or AxinΔp53 downregulates β-catenin and TCF-4, and knock-down of β-catenin upregulates TCF-4 in BE1 cells. However, expression of AxinΔβ-ca into BE1 cells did not downregulate TCF-4 expression. These results indicate that Axin downregulates TCF-4 transcription via β-catenin. Although overexpression of wild-type p53 also downregulates TCF-4 in BE1 cells, cotransfection of p53 and AxinΔβ-ca did not downregulate TCF-4 further. These results suggest that Axin does not promote p53-mediated downregulation of TCF-4. Axin, AxinΔp53, and AxinΔβ-ca all downregulated β-catenin and TCF-4 in A549 cells. Knock-down of p53 upregulated β-catenin and TCF-4, but cotransfection of AxinΔβ-ca and p53 siRNA resulted in downregulation of β-catenin and TCF-4. These results indicate that p53 is not required for Axin-mediated downregulation of TCF-4. Knock-down or inhibition of GSK-3β prevented Axin-mediated downregulation of TCF-4. Furthermore, expression of Axin and AxinΔp53, prevented the proliferative and invasive ability of BE1 and A549, expression of AxinΔβ-ca could only prevented the proliferative and invasive ability effectively. Axin downregulates TCF-4 transcription via β-catenin and independently of p53. Axin may also inhibits the proliferation and invasion of lung cancer cells via β-catenin and p53.
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